Substituted pyrrolo-aminopyrimidine compounds

Abstract

The present invention relates to substituted pyrrolo-aminopyrimidine compounds and methods of synthesizing these compounds. The present invention also relates to pharmaceutical compositions containing substituted pyrrolo-aminopyrimidine compounds and methods of treating cell proliferative disorders, such as cancer, by administering these compounds and pharmaceutical compositions to subjects in need thereof. The substituted pyrrolo-aminopyrimidine compounds have the following general formula:

What is claimed is: 
     
       1. A compound of Formula I, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 X is CH or N; 
 R 1  is H or unsubstituted or substituted C 1 -C 6  alkyl; 
 R a1  and R a2  are each independently H, —NHR 2 , —(CH 2 ) m YR 2 , —C(O)YR 2 , —NHC(O)R 2 , halogen, —NHC(O)NHR 2 , unsubstituted or substituted C 1 -C 6  alkyl, unsubstituted or substituted C 6 -C 10  aryl, unsubstituted or substituted C 3 -C 10  carbocycle, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or 
 when adjacent, R a1  and R a2 , together with the carbon atoms to which they are attached, form an unsubstituted or substituted aryl comprising one or two 5- or 6-member rings, an unsubstituted or substituted C 3 -C 8  carbocycle, an unsubstituted or substituted heteroaryl comprising one or two 5- to 6-member rings which comprises 1-4 heteroatoms selected from N, O and S, or an unsubstituted or substituted heterocycle comprising one or two 5- to 6-member rings which comprises 1-4 heteroatoms selected from N, O and S; 
 R 2  is H, unsubstituted or substituted C 1 -C 6  alkyl, unsubstituted or substituted C 1 -C 6  alkoxy, unsubstituted or substituted C 1 -C 6  alkoxycarbonyl, unsubstituted or substituted aminocarbonyl, unsubstituted or substituted C 1 -C 6  alkylcarbonylamino, unsubstituted or substituted di-C 1 -C 6 -alkylamino, unsubstituted or substituted C 6 -C 10  aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10  carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or R 2  and Z, together with the nitrogen atom to which they are attached, form a 5- or 6-member ring which optionally comprises 1-3 additional heteroatoms selected from N, O and S and is optionally substituted; 
 Y is NH, NZ or O, provided that when Y is NZ, then Z and R 2 , together with the nitrogen atom to which they are attached, form a 5- or 6-member ring which optionally comprises 1-3 additional heteroatoms selected from N, O and S and is optionally substituted; 
 m is 0, 1, 2 or 3; 
 R b1 , R b2 , R b3 , R b4  and R b5  are each independently H, halogen, cyano, nitro, unsubstituted or substituted C 1 -C 6  alkyl, unsubstituted or substituted C 6 -C 10  aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10  carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, —(CH 2 ) p OR 3 , or 
 any two adjacent of R b1 , R b2 , R b3 , R b4  and R b5 , together with the carbon atoms to which they are attached, form an unsubstituted or substituted aryl comprising one or two 5- or 6-member rings, an unsubstituted or substituted C 3 -C 8  carbocycle, an unsubstituted or substituted heteroaryl comprising one or two 5- to 6-member rings which comprises 1-4 heteroatoms selected from N, O and S, or an unsubstituted or substituted heterocycle comprising one or two 5- to 6-member rings which comprises 1-4 heteroatoms selected from N, O and S; 
 R 3  is H, unsubstituted or substituted C 1 -C 6  alkyl, unsubstituted or substituted C 6 -C 10  aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10  carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; and 
 p is 0, 1, 2, 3 or 4. 
 
     
     
       2. The compound of  claim 1 , wherein X is CH and R 1  is H. 
     
     
       3. The compound of  claim 2 , wherein R a1  is —NHC(O)R 2 . 
     
     
       4. The compound of  claim 2 , wherein R a1  is —C(O)YR 2 . 
     
     
       5. A compound of Formula II, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H or unsubstituted or substituted C 1 -C 6  alkyl; 
 T is unsubstituted or substituted C 1 -C 6  alkyl linker or a bond; 
 Q is H, halogen, cyano, nitro, unsubstituted or substituted C 1 -C 6  alkyl, halogen substituted C 1 -C 6  alkyl, unsubstituted or substituted C 6 -C 10  aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10  carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, OR 5 , NR 5 R 6 , NR 6 C(O)R 5 , NR 6 C(O)OR 5 , NHC(O)NR 5 R 6 , C(O)R 5 , C(O)OR 5 , C(O)NR 5 R 6  or NHS(O) 2 R 5 ; 
 R b1 , R b2 , R b3 , R b4  and R b5  are each independently H, halogen, cyano, nitro, unsubstituted or substituted C 1 -C 6  alkyl, unsubstituted or substituted C 6 -C 10  aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10  carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, —(CH 2 ) p OR 3 , or 
 any two adjacent of R b1 , R b2 , R b3 , R b4  and R b5 , together with the carbon atoms to which they are attached, form an unsubstituted or substituted aryl comprising one or two 5- or 6-member rings, an unsubstituted or substituted C 3 -C 8  carbocycle, an unsubstituted or substituted heteroaryl comprising one or two 5- to 6-member rings which comprises 1-4 heteroatoms selected from N, O and S, or an unsubstituted or substituted heterocycle comprising one or two 5- to 6-member rings which comprises 1-4 heteroatoms selected from N, O and S; 
 R 3 , R 5  and R 6  are each independently H, unsubstituted or substituted C 1 -C 6  alkyl, unsubstituted or substituted C 6 -C 10  aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10  carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or R 5  and R 6 , together with the nitrogen atom to which they are attached, form a 5- or 6-member ring which optionally comprises 1-3 additional heteroatoms selected from N, O and S and is optionally substituted; and 
 p is 0, 1, 2, 3 or 4. 
 
     
     
       6. The compound of  claim 5 , wherein R 1  is H. 
     
     
       7. The compound of  claim 6 , wherein Q is unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S. 
     
     
       8. The compound of  claim 6 , wherein Q is unsubstituted or substituted C 1 -C 6  alkyl. 
     
     
       9. A compound of Formula III, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H or unsubstituted or substituted C 1 -C 6  alkyl; 
 T is unsubstituted or substituted C 1 -C 6  alkyl linker or a bond; 
 Q is H, halogen, cyano, nitro, unsubstituted or substituted C 1 -C 6  alkyl, halogen substituted C 1 -C 6  alkyl, unsubstituted or substituted C 6 -C 10  aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10  carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, OR 5 , NR 5 R 6 , NR 6 C(O)R 5 , NR 6 C(O)OR 5 , NHC(O)NR 5 R 6 , C(O)R 5 , C(O)OR 5 , C(O)NR 5 R 6  or NHS(O) 2 R 5 ; 
 R b1 , R b2 , R b3 , R b4  and R b5  are each independently H, halogen, cyano, nitro, unsubstituted or substituted C 1 -C 6  alkyl, unsubstituted or substituted C 6 -C 10  aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10  carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, —(CH 2 ) p OR 3 , or 
 any two adjacent of R b1 , R b2 , R b3 , R b4  and R b5 , together with the carbon atoms to which they are attached, form an unsubstituted or substituted aryl comprising one or two 5- or 6-member rings, an unsubstituted or substituted C 3 -C 8  carbocycle, an unsubstituted or substituted heteroaryl comprising one or two 5- to 6-member rings which comprises 1-4 heteroatoms selected from N, O and S, or an unsubstituted or substituted heterocycle comprising one or two 5- to 6-member rings which comprises 1-4 heteroatoms selected from N, O and S; 
 R 3 , R 5  and R 6  are each independently H, unsubstituted or substituted C 1 -C 6  alkyl, unsubstituted or substituted C 6 -C 10  aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10  carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or R 5  and R 6 , together with the nitrogen atom to which they are attached, form a 5- or 6-member ring which optionally comprises 1-3 additional heteroatoms selected from N, O and S and is optionally substituted; and 
 p is 0, 1, 2, 3 or 4. 
 
     
     
       10. The compound of  claim 9 , wherein R 1  is H. 
     
     
       11. The compound of  claim 10 , wherein Q is unsubstituted or substituted phenyl. 
     
     
       12. The compound of  claim 10 , wherein Q is unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S. 
     
     
       13. A compound of Formula IV, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H or unsubstituted or substituted C 1 -C 6  alkyl; 
 T is unsubstituted or substituted C 1 -C 6  alkyl linker or a bond; 
 Q is H, halogen, cyano, nitro, unsubstituted or substituted C 1 -C 6  alkyl, halogen substituted C 1 -C 6  alkyl, unsubstituted or substituted C 6 -C 10  aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10  carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, OR 5 , NR 5 R 6 , NR 6 C(O)R 5 , NR 6 C(O)OR 5 , NHC(O)NR 5 R 6 , C(O)R 5 , C(O)OR 5 , C(O)NR 5 R 6  or NHS(O) 2 R 5 ; 
 R b1 , R b2 , R b3 , R b4  and R b5  are each independently H, halogen, cyano, nitro, unsubstituted or substituted C 1 -C 6  alkyl, unsubstituted or substituted C 6 -C 10  aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10  carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, —(CH 2 ) p OR 3 , or 
 any two adjacent of R b1 , R b2 , R b3 , R b4  and R b5 , together with the carbon atoms to which they are attached, form an unsubstituted or substituted aryl comprising one or two 5- or 6-member rings, an unsubstituted or substituted C 3 -C 8  carbocycle, an unsubstituted or substituted heteroaryl comprising one or two 5- to 6-member rings which comprises 1-4 heteroatoms selected from N, O and S, or an unsubstituted or substituted heterocycle comprising one or two 5- to 6-member rings which comprises 1-4 heteroatoms selected from N, O and S; 
 R 3 , R 5  and R 6  are each independently H, unsubstituted or substituted C 1 -C 6  alkyl, unsubstituted or substituted C 6 -C 10  aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10  carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or R 5  and R 6 , together with the nitrogen atom to which they are attached, form a 5- or 6-member ring which optionally comprises 1-3 additional heteroatoms selected from N, O and S and is optionally substituted; and 
 p is 0, 1, 2, 3 or 4. 
 
     
     
       14. The compound of  claim 13 , wherein R 1  is H. 
     
     
       15. The compound of  claim 14 , wherein Q is unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S. 
     
     
       16. The compound of  claim 14 , wherein Q is unsubstituted or substituted di-C 1 -C 6 -alkylamino. 
     
     
       17. A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       18. A pharmaceutical composition comprising a compound of  claim 5  and a pharmaceutically acceptable carrier. 
     
     
       19. A pharmaceutical composition comprising a compound of  claim 9  and a pharmaceutically acceptable carrier. 
     
     
       20. A pharmaceutical composition comprising a compound of  claim 13  and a pharmaceutically acceptable carrier. 
     
     
       21. A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       22. A pharmaceutical composition comprising a compound of  claim 21  and a pharmaceutically acceptable carrier. 
     
     
       23. A compound: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       24. A pharmaceutical composition comprising the compound of  claim 23  and a pharmaceutically acceptable carrier.